Extended Data Fig. 2: Schematic illustrating key concepts in the paper.

(A) Illustration of the liability threshold model for rare neurodevelopmental conditions. The figure shows why one might expect patients with a monogenic diagnosis to have less polygenic (common variant) risk than those without a monogenic diagnosis. The normal distribution represents the underlying distribution of liability in the population, which is assumed to be Gaussian. Both genetic and environmental factors of different effects contribute to this total liability. Each panel represents a hypothetical example of one individual, either unaffected, affected and diagnosed with a monogenic cause, or affected and without a monogenic diagnosis. The red line indicates a threshold for being diagnosed with neurodevelopmental conditions. Circles represent different genetic factors, and diamonds represent environmental factors. The size of circles and diamonds represents their impact on disease risk. The second patient, who has a monogenic diagnosis, has fewer green circles (fewer NDC risk-increasing common variants) than the undiagnosed patient on the right, since the orange circle (diagnostic large-effect variant) is sufficient on its own to push the diagnosed patient over the diagnostic threshold. (B) Illustration of how parental assortment leads to correlation between the common and rare variant components of risk for neurodevelopmental conditions. The figure shows three hypothetical families in which the mother in each pair has a similar level of cognitive ability/educational attainment to the father (a phenomenon called parental assortment). Mother and father from the same family also have similar genetic predispositions towards these traits and hence also towards risk of NDCs. Numbers on the bottom of each jar represents the simulated count of risk alleles from NDC-associated common variants represented by green circles (PGS) and that from NDC-associated rare variants represented by blue circles (RVBS). In the lefthand two families, both parents have a low risk for NDCs, as shown by the total height of the blue and green circles being well below the liability threshold indicated by the red line. Children in these two families have inherited about the expected number of parental common and rare variant risk alleles (the average of their parents) and also have low risk for developing NDCs. In the third family, both parents are not clinically affected by NDCs but both have subclinical phenotypes (for example, mild learning difficulties) due to having more risk alleles at rare (lefthand parent) or common (righthand parent) variants which contribute to reduced cognitive performance. Their child’s risk is above the diagnostic threshold indicated by the red line. In the parents’ generation, when parental assortment starts, there is no significant correlation between PGS and RVBS (two-sided P = 0.87, Pearson correlation r = 0.08 using the simulated counts). In their children, those who have more polygenic risk also tend to have more rare variant risk (correlation between PGS and RVBS is significant with P = 0.023, r = 0.999). Note that the values for PGS and RVBS have been chosen deliberately to emphasize the point for illustrative purposes, but the correlation in the child is much weaker than this in reality (Fig. 5). Also note that when analysing the real data, we regressed out principal components from PGS and RVBS before calculating the correlations.